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Journal of Virology, March 2006, p. 2675-2683, Vol. 80, No. 6
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.6.2675-2683.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.

Inhibition of Interferon Signaling by Rabies Virus Phosphoprotein P: Activation-Dependent Binding of STAT1 and STAT2

Krzysztof Brzózka, Stefan Finke, and Karl-Klaus Conzelmann*

Max von Pettenkofer Institute and Gene Center, Ludwig-Maximilians-University, D-81377 Munich, Germany

Received 27 October 2005/ Accepted 21 December 2005

Rabies virus (RV) phosphoprotein P is an interferon (IFN) antagonist counteracting transcriptional activation of type I IFN (K. Brzózka, S. Finke, and K. K. Conzelmann, J. Virol 79:7673-7681, 2005). We here show that RV P in addition is responsible for preventing IFN-{alpha}/ß- and IFN-{gamma}-stimulated JAK-STAT signaling in RV-infected cells by the retention of activated STATs in the cytoplasm. Expression of IFN-stimulated response element- and gamma-activated sequence-controlled genes was severely impaired in cells infected with RV SAD L16 or in cells expressing RV P protein from transfected plasmids. In contrast, a recombinant RV expressing small amounts of P had lost the ability to interfere with JAK-STAT signaling. IFN-mediated tyrosine phosphorylation of STAT1 and STAT2 was not impaired in RV P-expressing cells; rather, a defect in STAT recycling was suggested by distinct accumulation of tyrosine-phosphorylated STATs in cell extracts. In the presence of P, activated STAT1 and STAT2 were unable to accumulate in the nucleus. Notably, STAT1 and STAT2 were coprecipitated with RV P only from extracts of cells previously stimulated with IFN-{alpha} or IFN-{gamma}, whereas in nonstimulated cells no association of P with STATs was observed. This conditional, IFN activation-dependent binding of tyrosine-phosphorylated STATs by RV P is unique for a viral IFN antagonist. The 10 C-terminal residues of P are required for counteracting JAK-STAT signaling but not for inhibition of transcriptional activation of IFN-ß, thus demonstrating two independent functions of RV P in counteracting the host's IFN response.

* Corresponding author. Mailing address: Max von Pettenkofer Institute and Gene Center, Feodor Lynen Str. 25, D-81377 Munich, Germany, Phone: 49 89 2180 76851. Fax: 49 89 2180 76899. E-mail: conzelma{at}lmb.uni-muenchen.de.

Journal of Virology, March 2006, p. 2675-2683, Vol. 80, No. 6
0022-538X/06/$08.00+0     doi:10.1128/JVI.80.6.2675-2683.2006
Copyright © 2006, American Society for Microbiology. All Rights Reserved.



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